1. Use MRI visualization to measure the concentration distribution of different drug surrogates/contrast agents following intravitreal injection in ex vivo bovine eyes. 2. Apply a mathematical model to match the concentration distribution data with theoretical prediction, and obtain by minimum deviation (least squares fit) the value of the diffusion coefficient for each surrogate. 3. Compare the diffusion coefficient for the different contrast agents in relation to their molecular masses.

Methods

Fresh bovine eyes (source: Manning Beef, Pico Rivera, CA) were used for surrogate drug diffusion in the vitreous, and two compounds (Gd-DTPA and Prohance) were used as surrogates/contrast agents to visualize the diffusion process by MRI. Experiments were conducted by injecting 30 μl of each compound, diluted with 0.9% saline, separately in the vitreous of a whole eye. The initial concentrations were 20 mM/l for Gd-DTPA and 10 mM/l for Prohance. Imaging was conducted at 25-40 min intervals for up to 2.5 hours, and the concentration profiles for the two compounds were obtained at the different times.

Results

Following the method developed earlier, contours of constant concentration were established for each eye, and the comparison of these with the corresponding theoretical calculation for the same initial conditions, the diffusion coefficients values were acquired to an accuracy of 10% based on the standard deviation. We have made a comparison of previously-reported results for Gd-DTPA with current investigation on Prohance, and found for the diffusion coefficient, Gd-DTPA (mol wt 938): 3 × 10-6 cm2 /s Prohance: (mol wt 559): 4 × 10-6 cm2/s

Conclusions

The contour method recently developed for the diffusion coefficient measurement is a very useful technique for accurate values. This is one of the building blocks towards a comprehensive database of the diffusion coefficient in ocular tissue, and a step towards sound predictive ocular drug-delivery mathematical model. It is of interest to correlate the data with molecular weight for various compounds. With the firm establishment of the technique, we are able to show a comparison of Prohance with Gd-DTPA. While the smaller molecule has a higher diffusion coefficient, as expected, the effect of net charge on Gd-DTPA appears to be likely.